CN1333778A - Benzylmaltotriosides as inhibitors of smooth muscle cell proliferation - Google Patents
Benzylmaltotriosides as inhibitors of smooth muscle cell proliferation Download PDFInfo
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Abstract
This invention provides smooth muscle cell proliferation inhibitors of formula (I) having the structure wherein X is (A) wherein R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8>, R<9> and R<10>, are each, independently, hydrogen, acyl of 2-7 carbon atoms, perfluoroacyl of 2-10 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, benzoyl, benzyl or -SO3M; M is hydrogen, lithium, sodium, potassium or ammonium; R<11> is hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atomes, halogen, nitrile, nitro, or alkoxy of 1-6 carbon atoms; R<12> is hydrogen, nitro, amino, acylamino of 2-7 carbon atoms, perfluoroacylamino of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, perfluoroalkylamino of 1-6 carbon atoms, dialklylamino where each alkyl chain is independently 1-6 carbon atoms, perfluorodialklylamino where each alkyl chain is independently 1-6 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms, perfluoroalkyl-sulfonylamino of 1-6 carbon atoms, arylsulfonylamino of 6-10 carbon atoms or arylsulfonylamino substituted with halo of 6-10 carbon atoms; or a pharmaceutically acceptable salt thereof.
Description
Background of the present invention
The benzyl maltotriosides that the present invention relates to replace is for example purposes of the therapeutic composition of restenosis of the disease of feature and symptom as the purposes of inhibitors of smooth muscle cell proliferation with as treatment with excessive proliferation of smooth muscle.
All reconstructing blood vessel modes are the process of angioplasty and venous shunt art for example, all causes the reaction to damage, finally causes deposition (Clowes, the A.W. of smooth muscle cell (SMC) propagation and a large amount of extracellular matrixs subsequently; Reidy, M.A.J.Vasc.Surg 1991,13, and 885).These situations also are atherosclerosis (Raines E.W.; Ross R.Br.Heart J.1993,69 (supplementary issues), S.30) and transplant arteriosclerosis (Isik, F.F.; McDonald, T.O.; Ferguson, M.; Yamanaka, E.; Gordon Am.J.Pathol.1992,141,1139) pathogenetic main process.About the restenosis of postangioplasty, clinical relevant solution by medicine intervention control SMC propagation still exists elusive problem (Herrman, J.P.R. so far; Hermans, W.R.M.; Vos, J.; Serruys P.W.Drugs 1993,4,18 and 249).The method that any successful selectivity SMC propagation suppresses must not hinder function (Weissberg, the P.L. of endotheliocyte reparation or normal propagation and other cell; Grainger, D.J.; Shanahan C.M.; Metcalfe, J.C.Cardiovascular Res.1993,27,1191).
Glycosaminoglycan heparin and Suleparoid are the endogenous inhibitor of SMC propagation, can promote growth (Castellot, the J.J.Jr. of endotheliocyte in addition; Wright, T.C.; Kamovsky, M.J.Seminars in Thrombosis and Hemostasis 1987,13,489).Yet, because the unfavorable factor of other pharmacology relevant (particularly because anticoagulation causes excessive hemorrhage) with the heterogeneity of many preparations, make the heparin of heparin, heparin fragment, chemical modification, low-molecular-weight heparin and the intact clinical effectiveness of other heparin mimicking anionic polysaccharide (Borman that suffers damage, S.Chemical and Engineering News, 1993, June 28,27).
WO96/14325 discloses the benzyl glycosides as the acidylate of inhibitors of smooth muscle cell proliferation.Compound of the present invention different with it in the following areas (a) sugar moieties is that trisaccharide maltose is with (b) substituting group on sugar backbone is different in essence.
Zehavi, U. be at Carbohyd.Res.1986, discloses 4-carboxyl-2-nitrobenzyl 4-O-α-D-glucopyranosyl-β-D-glucopyranoside in 151,371, and this compound is connected and is used for the polymkeric substance of glycogen synthase repercussion study as acceptor.Compound of the present invention is different with it in the following areas: (a) sugar moieties is a trisaccharide maltose, and (b) substituting group on benzyl group is different different with (c) its effect (unstriated muscle antiproliferative).
Patent No. US5,498,775, WO96/14324 and US5,464,827 disclose polyanion benzyl glycosides or cyclodextrin as inhibitors of smooth muscle cell proliferation, and being used for the treatment of with excessive proliferation of smooth muscle is the disease and the symptom of feature.At (Reilly, C.F.; Fujita, T.; McFall, R.C.; Stabilito, I.I.; Wai-se E.; Beta-cyclodextrin 14 sulfuric esters are disclosed Johnson, R.G.Drug Development Research 1993,29,137) as inhibitors of smooth muscle cell proliferation with as effective inhibitor of restenosis.US5019562 discloses the anionic derivative of cyclodextrin, is used for the treatment of the pathological symptom relevant with unwanted cells or tissue growth.WO93/09790 discloses the antiproliferative polyanionically-derivatised thing that each saccharide residue has the cyclodextrin of at least 2 negatively charged ion residues.The antithrombotic of Meinetsberger (EP312087A2 and EP312086A2) discloses sulfation two-glyconic acid acid amides forms and anticoagulant characteristic.US4431637 discloses the conditioning agent of poly-sulfation phenolic glycoside as complement system.The difference of compound of the present invention and prior art is: this compound (a) be with heparin, sulfated cyclodextrin or sulfation lactobionic acid dimeric structure on dissimilar benzyl maltotriosides, (b) contain the saccharide residue (trisaccharide) that is no more than three connections and (c) be the structure of determining.
Explanation of the present invention
The invention provides benzyl maltotriosides or its pharmacy acceptable salt of formula I
Wherein X is
R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9And R
10Each independently is hydrogen, have the acyl group of 2-7 carbon atom, have the perfluoro acidyl of 2-10 carbon atom, the alkyl with 1-6 carbon atom, perfluoroalkyl, benzoyl, benzyl with 1-6 carbon atom or-SO
3M; M is hydrogen, lithium, sodium, potassium or ammonium; R
11Be hydrogen, have the alkyl of 1-6 carbon atom, perfluoroalkyl, halogen, nitrile, nitro or have the alkoxyl group of 1-6 carbon atom with 1-6 carbon atom; R
12Be hydrogen; nitro; amino; amido with 2-7 carbon atom; perfluor amido with 2-7 carbon atom; alkylamino with 1-6 carbon atom; perfluoroalkyl amino with 1-6 carbon atom; wherein each alkyl chain independently is the dialkyl amido of 1-6 carbon atom; wherein each alkyl chain independently is the perfluor dialkyl amido of 1-6 carbon atom; alkyl sulfonyl-amino with 1-6 carbon atom; perfluoroalkyl group sulfonyl amino with 1-6 carbon atom; have the arlysulfonylamino of 6-10 carbon atom or the arlysulfonylamino that replaces by halo with 6-10 carbon atom.
Alkyl, alkoxyl group, alkyl sulfonyl-amino, amido and acyl group comprise an optional straight chain and a chain portion that is replaced by fluorine.Halogen is meant bromine, chlorine, fluorine and iodine.That aryl is defined as is undersaturated fully, contain the carbocylic radical of the optional one or more rings with 6-10 carbon atom that replaced by fluorine; Wherein preferred phenyl and naphthyl.
Pharmacy acceptable salt can be formed by organic and inorganic acid, for example acetate, propionic acid, lactic acid, citric acid, tartrate, succsinic acid, fumaric acid, toxilic acid, propanedioic acid, amygdalic acid, oxysuccinic acid, phthalic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methylsulfonic acid, naphthene sulfonic acid, Phenylsulfonic acid, toluenesulphonic acids, camphorsulfonic acid and similar known acceptable acid.Salt also can form preferred as alkali salt, for example sodium, lithium or sylvite by organic and mineral alkali.When the compound of formula I contains basic nitrogen, can prepare acid salt, when the compound of formula I contains hydroxyl, generally can prepare base addition salt.
Compound of the present invention can contain an asymmetric carbon atoms and some compounds of the present invention can contain one or more asymmetric centers, therefore can produce optical isomer and diastereomer.Although do not demonstrate stereochemistry among the formula I, the present invention includes these optical isomers and diastereomer; And racemic and that split, enantiomeric pure R and S steric isomer; And the mixture of other described R and S steric isomer and its pharmacy acceptable salt.
The preferred compound of the present invention is benzyl maltoside or its pharmacy acceptable salt of formula I
Wherein X is
R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9And R
10Each independently is hydrogen, have 2-7 carbon atom acyl group or-SO
3M; M is lithium, sodium, potassium or ammonium; R
11It is halogen; R
12Be nitro, amino or amido with 2-7 carbon atom.
The preferred compound of the present invention is benzyl maltoside or its pharmacy acceptable salt of formula I
Wherein X is
R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9And R
10Each independently be hydrogen, ethanoyl or-SO
3M; M is lithium, sodium, potassium or ammonium; R
11It is chloro; R
12Be hydrogen, nitro, amino or kharophen.
The particularly preferred compound of the present invention is:
5-(ten-O-ethanoyl-β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-1-oil of mirbane or its pharmacy acceptable salt;
N-[5-(ten-O-ethanoyl-β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-phenyl]-ethanamide or its pharmacy acceptable salt;
N-[5-(β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-phenyl]-ethanamide or its pharmacy acceptable salt;
N-[5-(ten-O-sulfo group-β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-phenyl]-ethanamide ten sodium salts or its pharmacy acceptable salt; And 5-(β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-aniline or its pharmacy acceptable salt.
The raw material of compound of the present invention from buying the raw material that obtains or can preparing with the method for document is according to following scheme preparation.This scheme is represented the preparation of the representational compound of the present invention.
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11And R
12As defined above.
So, at catalyzer for example in the presence of mercuric bromide, mercury cyanide, silver trifluoromethanesulfonate or the silver perchlorate, at aprotic solvent for example in acetonitrile, methylene dichloride, ether, toluene or the Nitromethane 99Min., in temperature range, make trisaccharide maltose bromide 1 and benzyl alcohol 2 couplings obtain glucosides 3 from-40 ℃ to backflow.With reductive agent tin protochloride for example, at polar aprotic solvent for example in the ethyl acetate, to the temperature that refluxes or by at catalyzer catalytic hydrogenation in the presence of the palladium on carbon for example, finish the reduction of 3 nitro in room temperature, obtain anilino compound 4.At amine alkali for example in the presence of triethylamine, diisopropylethylamine or the pyridine, at aprotic solvent for example in methylene dichloride or the tetrahydrofuran (THF), in temperature range from-20 ℃ to room temperature, finish 4 with the coupling of acyl chlorides or SULPHURYL CHLORIDE, obtain acid amides 5.In room temperature to the temperature that refluxes, by with alkali for example the acetoxyl of the methanol solution hydrolysis replaceable 5 of methanol solution of sodium methylate or aqueous sodium hydroxide obtain 6.At polar aprotic solvent for example in dimethyl formamide or the dimethyl sulfoxide (DMSO), in temperature range from 0 ℃ to 100 ℃, free hydroxyl group on some or all sugar with reagent for example sulphur trioxide-Trimethylamine 99 complex compound or sulphur trioxide-pyridine complex sulfation, is obtained compound 7.
Compound of the present invention is as antiproliferative.Following method demonstrates with the evaluation of standard pharmacology test method to representative compounds of the present invention, and the compound that described test determination is evaluated is to suppressing the ability of smooth muscle cell proliferation.With
3The H Thymine deoxyriboside is in conjunction with the effect of test determination compound on cell proliferation
Under (sub-confluent) culture condition of minute joining, (generally pass 3-7 generation) test person and pig smooth muscle cell down in early days goes down to posterity.Culture is grown in the 16mm that contains the substratum 199 of adding 10% foetal calf serum and 2% microbiotic/anti-mycotic agent (24 hole) porous culture dish.Fashionable in branch, cell is placed on definite serum free medium (AIM-V; Gibco) continue 24-48 hour in, start experiment flow then.
Can make compound more effective although find to prolong the preincubation phase, general by with compound,
3H Thymine deoxyriboside and serum/somatomedin join in the synchronous cell that does not contain serum the described process of starting and report the result thus.
In each hole, add 50 times of dilution compounds (20 μ L/ hole), and under 37 ℃ at 5%CO
2In, with dull and stereotyped incubation 24-36 hour.Earlier with compound dissolution in 50% ethanol and serial dilution in substratum.The compound of conventional evaluation 1-100 μ M concentration.In contrast, II level pig intestinal mucosa heparin (sodium salt) in all cells goods of conventional evaluation 0-1-100 μ g/mL concentration.
When experimentation finishes, flat board is placed on ice, with ice-cold phosphate-buffered saline (PBS) washing three times and in ice-cold 10% trichoroacetic acid(TCA) (TCA) incubation 30 minutes with except that the disacidify soluble protein.Transfer to solution in the scintillation vial that contains 0.4N HCl (500 μ L/ bottles with in and NaOH) and water (500 μ L with total amount 2mL/ bottle with twice of every hole rinsing.
Obtain triplicate data, contrast and laboratory sample are all like this.From the cell of maximal stimulation, obtain contrast (100%) data, as the result of somatomedin or serum stimulation.From with obtaining experimental data cell somatomedin or serum maximal stimulation and with compound treatment.Following Table I is represented with IC
50The data of expressing.
Table 1
| The embodiment compound | Pig smooth muscle cell antiproliferative IC50 |
| ????1 | ????1.8μM |
| ????2 | ????22.5μM |
| ????3 | 10% inhibiting rate is in 500 μ M |
| ????4 | ????111.7μM |
| ????5 | 25% inhibiting rate is in 500 μ M |
It is the disease of feature that compound of the present invention is used for the treatment of or suppresses with over-drastic smooth muscle cell proliferation (smooth muscle cell proliferation is too much).This compound is particularly useful for treating the vascular disease of crossing the hyperproliferative that mostly is feature with smooth muscle cell proliferation, restenosis for example, described disease is many by vascular reconstructive surgery and transplantation, and for example balloon angioplasty, blood vessel grafting, coronary bypass-forming operation and cardiac transplantation cause.Other disease refers to have the disease of undesirable " cell " blood vessel hyperplasia, comprises hypertension, asthma and congestive heart failure.Compound of the present invention also is used as the inhibitor of vasculogenesis.Vasculogenesis (neovascularization) promptly by its process that forms new capillary vessel, comprises that for some the pathologic process of chronic inflammatory diseases and malignant tumour is particularly important.Therefore compound of the present invention is as antitumour drug.
Compound of the present invention can be mixed with pure preparation or prepare administration with pharmaceutical carrier, and its ratio depends on the pharmacy practice of the chemical property of solvability and compound, selected route of administration and standard.Described pharmaceutical carrier can be solid or liquid.
Solid carrier can comprise one or more materials, and this material can be used as seasonings, lubricant, solubilizing agent, suspension agent, weighting agent, glidants, compression aid, tackiness agent or tablet-disintegrating agent; It also can be encapsulating material.In powder, carrier is a solid in small, broken bits, and this solid mixes with activeconstituents in small, broken bits.In tablet, activeconstituents with have essential compressible carrier with suitable mixed, and be pressed into required shape and size.Powder and tablet preferably contain high to 99% activeconstituents.Suitable solid carrier comprises for example calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidone, low-melting wax and ion exchange resin.
Liquid support is used for obtain solution, suspension, emulsion, syrup, elixir and pressurized compositions.Activeconstituents solubilized or be suspended in pharmaceutically acceptable liquid vehicle for example in water, organic solvent, both mixture or pharmaceutically acceptable oil or fat.This liquid vehicle can contain other suitable medicinal additive for example solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweeting agent, seasonings, suspension agent, thickening material, tinting material, viscosity modifier, stablizer or Osmolyte regulator.Be used for oral and suitable liquid vehicle example administered parenterally and comprise that (part contains aforesaid additive to water, derivatived cellulose for example, the preferably carboxymethyl cellulose sodium solution), alcohols (comprising monohydroxy-alcohol and polyvalent alcohol, for example dibasic alcohol) and their derivative, lethicins and oil (for example fractionated coconut oil and peanut oil).For administered parenterally, carrier also can be for example ethyl oleate and a Wickenol 101 of oily ester.Sterile liquid carrier is used to prepare the sterile liquid form composition of administered parenterally.Liquid vehicle for pressurized compositions can be halohydrocarbon or other pharmaceutically acceptable propellent.
For the liquid pharmaceutical composition of sterile solution or suspension can be used for for example intramuscular, intraperitoneal or subcutaneous injection.Sterile solution also can intravenously administrable.Compound of the present invention also can the liquid or solid composition the form oral administration.
Compound of the present invention can conventional suppository form rectum or intravaginal administration.For sucking in the nose or in the segmental bronchus or being blown into administration, compound of the present invention can be mixed with the solution of aqueous or partially aqueous, and the form that this solution can sprays is used.Compound of the present invention also can contain active compound and to the transdermal patch percutaneous dosing of active compound as the inert carrier by using, and this carrier is nontoxic to skin and allows to be used for the medicine that system absorbs and enter blood flow through skin-communication.This carrier can be prepared into some formulations for example emulsifiable paste and ointment, paste, gel and occlusive devices.Emulsifiable paste and ointment can be the viscous liquid or the semi-solid emulsion of oil-in-water or water-in-oil-type.By being dispersed in the paste that the sherwood oil that contains activeconstituents or the absorbent powder in the hydrophilic petroleum ether form also is suitable.Can use various occlusive devices to enter in the blood flow with release of active ingredients, for example covering contains activeconstituents, is with or without the storage of carrier, or contains the semi-permeable membranes of activeconstituents matrix.Other occlusive devices is known in the literature.
The dosage of administration needs to change according to the severity of employed concrete composition, route of administration, symptom and the concrete object of being treated.According to the result who from the standard pharmacological test method, obtains, should be 0.1-10mg/kg through the per daily dose of the expectation active compound of parenteral (preferred intravenously) administration, estimate that day oral dosage is than about ten times of this dosage height.After acute vascular damage (being balloon angioplasty or transplantation), the intravenous administration of expection will continue about 5-30 days and also want time expand for treatment of chronic diseases.General with the low dose of begin treatment lower than the optimal dose of compound.Increase dosage later on up to reaching best effect in this case; The actual dose that is used for administration in oral, parenteral, intranasal or the segmental bronchus, will by the doctor in charge rule of thumb with the situation decision of the individual patient of being treated.Medicinal compositions is preferably unit dosage form, for example tablet or capsule.In these formulations, said composition can be further divided into the unitary dose that contains an amount of activeconstituents; This unit dosage form can be a packaged composition, for example packaged powders, phial, ampoule, the syringe that is full of in advance or contain the sachet of liquid.This unit dosage form can be the packaged form of any this based composition of capsule or tablet itself or suitable quantity for example.
The preparation method of representative compounds of the present invention below is provided.
Embodiment 15-(ten-O-ethanoyl-β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-1-oil of mirbane
At room temperature, to stir contain 4-chloro-3-nitrobenzyl alcohol (5.48g, 0.0292mol), HgBr
2(11.82g, 0.0321mol) and Hg (CN)
2(7.45g, CH 0.0292mol)
3NO
2Solution in add acetyl bromide for trisaccharide maltose (28.85g, 0.0292mol).After 16 hours, use CH
2Cl
2(500mL) the diluting reaction thing is also by 1 " filtration of sulka fioc pad, use CH
2Cl
2Rinsing.With salt solution (3 * 1L) wash filtrates, dry (MgSO
4) and concentrate.Purifying on silica gel is with 0,1,2 and 3%MeOH/CHCl
3Gradient elution obtains the 11.64g title compound, is white solid, mp85-100 ℃;
1H NMR (DMSO-d
6) δ 1.931 (s, 3H), 1.938 (s, 3H), 1.941 (s, 3H), 1.944 (s, 3H), 1.952 (s, 3H), 1.968 (s, 3H), 1.975 (s, 3H), 2.004 (s, 3H), 2.065 (s, 3H), 2.076 (s, 3H), 3.91-4.00 (m, 6H), 4.12-4.18 (m, 2H), 4.23 (dd, 1H), 4.35 (t, 2H), 4.68-4.99 (m, 7H), 5.17-5.34 (m, 5H), 7.59 (dd, 1H), 7.77 (d, 1H), 7.95 (s, 1H), IR (KBr) 2950,1750,1375,1230 and 1050cm
-1, mass spectrum (FAB), m/z 1094 (M+H).For C
45H
56NClO
28Calculated value: C, 49.39; H, 5.16; N, 1.28.Measured value: C, 49.08, H, 5.09, N, 1.27.
Embodiment 2N-[5-(ten-O-ethanoyl-β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-phenyl]-ethanamide
Step 15-(ten-O-ethanoyl-β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro aminobenzen
With stir contain 5-(ten-O-ethanoyl-β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-1-oil of mirbane (2.58g, 2.36mmol) and tin chloride (II) dihydrate (3.73g, the solution backflow of EtOAc 16.5mmol) (47mL) 1.5 hours.Reactant is cooled to room temperature, with saturated NaHCO
3(50mL) aqueous solution quencher carefully with EtOAc (50mL) dilution, was stirred 0.5 hour and was filtered.Separate two-phase filtrate and extract the waterbearing stratum with EtOAc.With the organic extract liquid drying (K that merges
2CO
3) and concentrate.Through silica gel purification, with 0,1 and 2%MeOH/CHCl
3Gradient elution obtains the title compound of 2.37g (94%), is white solid, mp85-100 ℃;
1H NMR (DMSO-d
6) δ 1.922 (s, 3H), 1.935 (s, 3H), 1.937 (s, 3H), 1.942 (s, 3H), 1.946 (s, 3H), 1.969 (s, 3H), 1.977 (s, 3H), 2.007 (s, 3H), 2.070 (s, 3H), 2.094 (s, 3H), 3.88-4.01 (m, 6H), and 4.13-4.18 (m, 2H), 4.24-4.28 (m, 1H), 4.32-4.39 (m, 3H), 4.59 (d, 1H), 4.67-4.86 (m, 4H), 4.97 (t, 1H), 5.17-5.38 (m, 7H), 6.43 (dd, 1H), 6.67 (d, 1H), 7.13 (d, 1H).IR (KBr) 3475,3375,2950,1750,1230 and 1040cm
-1, mass spectrum (FAB), m/z1064 (M+H).
Step 2N-[5-(ten-O-ethanoyl-β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-phenyl]-ethanamide
At room temperature; contain 5-(ten-O-ethanoyl-β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro aminobenzen (1.62g to what stir; 1.52mmol) and triethylamine (1.72mL, add in the solution of THF 12.3mmol) (15mL) Acetyl Chloride 98Min. (0.294mL, 4.12mmol) in.After 4 days, with saturated NaHCO
3Aqueous solution quencher reaction (40mL) extracts with salt solution (30mL) dilution and with EtOAc.With the organic extract liquid drying (K that merges
2CO
3) and concentrate.Through silica gel purification, with 1,2 and 3%MeOH/CHCl
3Gradient elution, chromatography obtains the 0.353g title compound with 50% acetone/hexane wash-out for the second time subsequently, is light yellow solid, mp93-100 ℃;
1H NMR (DMSO-d
6) δ 1.92-2.01 (m, 24H), 2.07 (s, 6H), 2.09 (s, 3H), 3.89-4.01 (m, 6H), 4.13-4.18 (m, 2H), 4.24-4.28 (m, 2H), 4.32-4.35 (m, 2H), 4.53 (d, 1H), 4.69-4.77 (m, 3H), 4.83-4.86 (m, 2H), 4.97 (t, 1H), 5.17-5.33 (m, 5H), 7.07 (dd, 1H), 7.45 (d, 1H), 7.62 (s, 1H), 9.51 (s, 1H).IR (KBr) 3425,1760,1230 and 1050cm
-1, mass spectrum (FAB), m/z 1106 (M+H).For C
47H
60NClO
27Calculated value: C, 51.02; H, 5.47; N, 1.27.Measured value: C, 50.92, H, 5.36, N, 1.38.
Embodiment 35-(β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-aniline
Contain N-[5-(ten-O-ethanoyl-β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-phenyl with what stir]-ethanamide (1.032g; 0.933mmol) and (0.101g, the solution of MeOH 0.467mmol) (30mL) refluxed 4.5 hours to be dissolved in 25 weight %NaOMe among the MeOH.Reactant is cooled to room temperature and concentrated.Through Dynamax C18 purifying, use 15%CH
3CN/H
2The O wash-out obtains the title compound of 0.428g (67%), is white solid, mp135-148 ℃;
1H NMR (DMSO-d
6) δ 2.07 (s, 3H), 3.02-3.11 (m, 2H), 3.20-3.49 (m, 9H), 3.53-3.66 (m, 6H), 3.69-3.73 (m, 1H), 4.27 (d, 1H), 4.49-4.57 (m, 4H), 4.80 (d, 1H), 4.85-4.87 (m, 2H), 4.98 (d, 1H), 5.02 (d, 1H), 5.24 (d, 1H), 5.45 (br, s, 2H), 5.52 (br, s, 2H), 7.21 (dd, 1H), 7.44 (d, 1H), 7.64 (s, 1H), 9.52 (s, 1H).IR (KBr) 3400,2900,1675 and 1030cm
-1, mass spectrum (FAB), m/z686 (M+H).For C
27H
40NClO
17H
2The calculated value of O: C, 46.06; H, 6.01; N, 1.99.Measured value: C, 46.07, H, 6.09, N, 1.99.
Embodiment 4N-[5-(ten-O-sulfo group-β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-phenyl]-ethanamide ten sodium salts
With stir contain 5-(β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-aniline (0.278g, 4.05mmol) and sulphur trioxide-Trimethylamine 99 complex compound (2.82g, the solution of DMF 20.3mmol) (20mL) is 70 ℃ of stirrings 48 hours down.Reactant is cooled to room temperature, and water (50mL) dilution is filtered and concentrated filtrate.Through Sephadex G-10 purifying, the water wash-out is gone up through cationic exchange at Dowex50 * Final 8's acidic resins (Na type) subsequently, obtains the title compound of 0.596g (86%), is white solid, mp173 ℃;
1H MR (H
2O-d
2) δ 2.09 (s, 3H), 3.93-4.28 (m, 11H), 4.38-4.48 (m, 2H), 4.49-4.57 (m, 2H), 4.60-4.69 (m, 2H), 4.76-4.85 (m, 4H), 5.40 (d, 1H), 5.50 (d, 1H), 7.29 (dd, 1H), 7.41-7.44 (m, 2H).IR (KBr) 3450,2950,1650 and 1250cm
-1, mass spectrum (FAB), m/z 1681 (M-H).For C
27H
30NClO
47Na
106H
2The calculated value of O: C, 17.87; H, 2.33; N, 0.77.Measured value: C, 17.84, H, 2.41, N, 0.78.
Embodiment 55-(β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-aniline
With 5-(ten-O-ethanoyl-β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro aminobenzen, the method by embodiment 3 prepares title compound, obtains the white solid of 0.225g (75%), mp95-134 ℃;
1H NMR (H
2O-d
2) δ 3.16-3.21 (m, 1H), 3.27 (t, 1H), 3.39-3.82 (m, 16H), 4.36 (d, 1H), 4.51 (d, 1H), 4.67 (d, 1H), 5.24 (t, 1H), 6.71 (dd, 1H), 6.85 (d, 1H), 7.20 (d, 1H).IR (KBr) 3400,2900,1625 and 1025cm
-1, mass spectrum (FAB), m/z 644 (M+H).For C
25H
38NClO
16H
2The calculated value of O: C, 45.36; H, 6.09; N, 2.12.Measured value: C, 45.37, H, 6.34, N, 2.05.
Claims (13)
1. formula I compound or its pharmacy acceptable salt with following structure
Wherein X is
R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9And R
10Each independently is hydrogen, have the acyl group of 2-7 carbon atom, have the perfluoro acidyl of 2-10 carbon atom, the alkyl with 1-6 carbon atom, perfluoroalkyl, benzoyl, benzyl with 1-6 carbon atom or-SO
3M; M is hydrogen, lithium, sodium, potassium or ammonium; R
11Be hydrogen, have the alkyl of 1-6 carbon atom, perfluoroalkyl, halogen, nitrile, nitro or have the alkoxyl group of 1-6 carbon atom with 1-6 carbon atom; R
12Be hydrogen; nitro; amino; amido with 2-7 carbon atom; perfluor amido with 2-7 carbon atom; alkylamino with 1-6 carbon atom; perfluoroalkyl amino with 1-6 carbon atom; wherein each alkyl chain independently is the dialkyl amido of 1-6 carbon atom; wherein each alkyl chain independently is the perfluor dialkyl amido of 1-6 carbon atom; alkyl sulfonyl-amino with 1-6 carbon atom; perfluoroalkyl group sulfonyl amino with 1-6 carbon atom; have the arlysulfonylamino of 6-10 carbon atom or the arlysulfonylamino that replaces by halo with 6-10 carbon atom.
2. according to compound or its pharmacy acceptable salt, the wherein R of claim 1
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9And R
10Each independently is hydrogen, have 2-7 carbon atom acyl group or-SO
3M; R
11Be hydrogen; R
12Be nitro, amino or amido with 2-7 carbon atom.
3. according to compound or its pharmacy acceptable salt, the wherein R of claim 2
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9And R
10Each independently be hydrogen, ethanoyl or-SO
3M; R
11It is chloro; R
12Be nitro, amino or kharophen.
4. according to the compound of claim 1, be 5-(ten-O-ethanoyl-β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-1-oil of mirbane or its pharmacy acceptable salt.
5. according to the compound of claim 1, be N-[5-(ten-O-ethanoyl-β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-phenyl]-ethanamide or its pharmacy acceptable salt.
6. according to the compound of claim 1, be N-[5-(β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-phenyl]-ethanamide or its pharmacy acceptable salt.
7. according to the compound of claim 1, be N-[5-(ten-O-sulfo group-β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-phenyl]-ethanamide ten sodium salts or its pharmacy acceptable salt.
8. according to the compound of claim 1, be 5-(β-D-trisaccharide maltose oxygen ylmethyl)-2-chloro-aniline or its pharmacy acceptable salt.
9. a method for the treatment of or suppressing the vascular disease of the mammiferous hyperplasia that needs this treatment comprises the formula I compound with following structure or its pharmacy acceptable salt that give described Mammals significant quantity
Wherein X is
R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9And R
10Each independently is hydrogen, have the acyl group of 2-7 carbon atom, have the perfluoro acidyl of 2-10 carbon atom, the alkyl with 1-6 carbon atom, perfluoroalkyl, benzoyl, benzyl with 1-6 carbon atom or-SO
3M; M is hydrogen, lithium, sodium, potassium or ammonium; R
11Be hydrogen, have the alkyl of 1-6 carbon atom, perfluoroalkyl, halogen, nitrile, nitro or have the alkoxyl group of 1-6 carbon atom with 1-6 carbon atom; R
12Be hydrogen; nitro; amino; amido with 2-7 carbon atom; perfluor amido with 2-7 carbon atom; alkylamino with 1-6 carbon atom; perfluoroalkyl amino with 1-6 carbon atom; wherein each alkyl chain independently is the dialkyl amido of 1-6 carbon atom; wherein each alkyl chain independently is the perfluor dialkyl amido of 1-6 carbon atom; alkyl sulfonyl-amino with 1-6 carbon atom; perfluoroalkyl group sulfonyl amino with 1-6 carbon atom; have the arlysulfonylamino of 6-10 carbon atom or have the arlysulfonylamino that replaces by halo of 6-10 carbon atom.
10. a method for the treatment of or suppressing the mammiferous restenosis that needs this treatment comprises the formula I compound with following structure or its pharmacy acceptable salt that give described Mammals significant quantity
Wherein X is
R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9And R
10Each independently is hydrogen, have the acyl group of 2-7 carbon atom, have the perfluoro acidyl of 2-10 carbon atom, the alkyl with 1-6 carbon atom, perfluoroalkyl, benzoyl, benzyl with 1-6 carbon atom or-SO
3M; M is hydrogen, lithium, sodium, potassium or ammonium; R
11Be hydrogen, have the alkyl of 1-6 carbon atom, perfluoroalkyl, halogen, nitrile, nitro or have the alkoxyl group of 1-6 carbon atom with 1-6 carbon atom; R
12Be hydrogen; nitro; amino; amido with 2-7 carbon atom; perfluor amido with 2-7 carbon atom; alkylamino with 1-6 carbon atom; perfluoroalkyl amino with 1-6 carbon atom; wherein each alkyl chain independently is the dialkyl amido of 1-6 carbon atom; wherein each alkyl chain independently is the perfluor dialkyl amido of 1-6 carbon atom; alkyl sulfonyl-amino with 1-6 carbon atom; perfluoroalkyl group sulfonyl amino with 1-6 carbon atom; have the arlysulfonylamino of 6-10 carbon atom or have the arlysulfonylamino that replaces by halo of 6-10 carbon atom.
11. according to the method for claim 10, wherein said restenosis is transplanted by angioplasty, vascular reconstructive surgery or organ or tissue and is caused.
12. a method that need to suppress mammiferous malignant tumour, sarcoma or the generation of tumor tissues medium vessels of this treatment comprises the formula I compound with following structure or its pharmacy acceptable salt that give described Mammals significant quantity
Wherein X is
R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9And R
10Each independently is hydrogen, have the acyl group of 2-7 carbon atom, have the perfluoro acidyl of 2-10 carbon atom, the alkyl with 1-6 carbon atom, perfluoroalkyl, benzoyl, benzyl with 1-6 carbon atom or-SO
3M; M is hydrogen, lithium, sodium, potassium or ammonium; R
11Be hydrogen, have the alkyl of 1-6 carbon atom, perfluoroalkyl, halogen, nitrile, nitro or have the alkoxyl group of 1-6 carbon atom with 1-6 carbon atom; R
12Be hydrogen; nitro; amino; amido with 2-7 carbon atom; perfluor amido with 2-7 carbon atom; alkylamino with 1-6 carbon atom; perfluoroalkyl amino with 1-6 carbon atom; wherein each alkyl chain independently is the dialkyl amido of 1-6 carbon atom; wherein each alkyl chain independently is the perfluor dialkyl amido of 1-6 carbon atom; alkyl sulfonyl-amino with 1-6 carbon atom; perfluoroalkyl group sulfonyl amino with 1-6 carbon atom; have the arlysulfonylamino of 6-10 carbon atom or have the arlysulfonylamino that replaces by halo of 6-10 carbon atom.
13. a medicinal compositions comprises formula I compound or its pharmacy acceptable salt and pharmaceutical carrier with following structure
Wherein X is
R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9And R
10Each independently is hydrogen, have the acyl group of 2-7 carbon atom, have the perfluoro acidyl of 2-10 carbon atom, the alkyl with 1-6 carbon atom, perfluoroalkyl, benzoyl, benzyl with 1-6 carbon atom or-SO
3M; M is hydrogen, lithium, sodium, potassium or ammonium; R
11Be hydrogen, have the alkyl of 1-6 carbon atom, perfluoroalkyl, halogen, nitrile, nitro or have the alkoxyl group of 1-6 carbon atom with 1-6 carbon atom; R
12Be hydrogen; nitro; amino; amido with 2-7 carbon atom; perfluor amido with 2-7 carbon atom; alkylamino with 1-6 carbon atom; perfluoroalkyl amino with 1-6 carbon atom; wherein each alkyl chain independently is the dialkyl amido of 1-6 carbon atom; wherein each alkyl chain independently is the perfluor dialkyl amido of 1-6 carbon atom; alkyl sulfonyl-amino with 1-6 carbon atom; perfluoroalkyl group sulfonyl amino with 1-6 carbon atom; have the arlysulfonylamino of 6-10 carbon atom or have the arlysulfonylamino that replaces by halo of 6-10 carbon atom.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US19880598A | 1998-11-24 | 1998-11-24 | |
| US09/198,805 | 1998-11-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1333778A true CN1333778A (en) | 2002-01-30 |
Family
ID=22734935
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99815706A Pending CN1333778A (en) | 1998-11-24 | 1999-11-23 | Benzylmaltotriosides as inhibitors of smooth muscle cell proliferation |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1133506A2 (en) |
| JP (1) | JP2002530420A (en) |
| CN (1) | CN1333778A (en) |
| AU (1) | AU1919800A (en) |
| BR (1) | BR9915643A (en) |
| CA (1) | CA2350759A1 (en) |
| WO (1) | WO2000031095A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040248945A1 (en) | 1999-04-23 | 2004-12-09 | Smithkline Beecham P.L.C. | Thiazolidinedione derivative and its use as antidiabetic |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL115745A (en) * | 1994-11-07 | 2000-11-21 | American Home Prod | Acylated benzylglycosides and pharmaceutical compositions containing them |
-
1999
- 1999-11-23 EP EP99962844A patent/EP1133506A2/en not_active Withdrawn
- 1999-11-23 CN CN99815706A patent/CN1333778A/en active Pending
- 1999-11-23 WO PCT/US1999/027775 patent/WO2000031095A2/en not_active Application Discontinuation
- 1999-11-23 AU AU19198/00A patent/AU1919800A/en not_active Abandoned
- 1999-11-23 CA CA002350759A patent/CA2350759A1/en not_active Abandoned
- 1999-11-23 BR BR9915643-1A patent/BR9915643A/en not_active Application Discontinuation
- 1999-11-23 JP JP2000583923A patent/JP2002530420A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002530420A (en) | 2002-09-17 |
| WO2000031095A2 (en) | 2000-06-02 |
| CA2350759A1 (en) | 2000-06-02 |
| AU1919800A (en) | 2000-06-13 |
| BR9915643A (en) | 2001-08-07 |
| EP1133506A2 (en) | 2001-09-19 |
| WO2000031095A3 (en) | 2001-01-04 |
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